Transcriptomic and epigenomic analysis of neuronal differentiation models of Kabuki Syndrome Type 1 [RNA-Seq]

Kabuki syndrome type 1 (KS1) is a neurodevelopmental disorder caused by loss-of-function variants in KMT2D which encodes a H3K4 methyltransferase. Here, we analysed transcriptomic differences across three stages of neuronal differentiation using patient-derived induced pluripotent stem cells (iPSCs). Overall, we identified hundreds of differentially expressed genes (DEGs) in iPSCs, NPs and CNs in KS1. We find that genes regulated by SUZ12, a subunit of Polycomb Repressive complex 2, are over-represented in KS1 DEGs at early stages of differentiation. We also identify loss of thousands of H3K4me1 peaks in iPSCs, neuronal progenitors (NPs) and early cortical neurons (CNs) in KS1. In conclusion, we present a disease-relevant human cellular model for KS1 that provides pathomechanistic insights of Kabuki Syndrome Type 1.